Liver HLA-G expression is associated with multiple clinical and histopathological forms of chronic hepatitis B virus infection

As the mechanisms leading to the persistence of hepatitis B virus (HBV) infection are poorly understood and as the histocompatibility leucocyte antigen (HLA)-G is well described as a tolerogenic molecule, we evaluated HLA-G expression in 74 specimens of HBV liver biopsies and in 10 specimens obtained from previously healthy cadaver liver donors. HBV specimens were reviewed and classified by the METAVIR score, and HLA-G expression was assessed by immunohistochemistry. No HLA-G expression was observed in control hepatocytes. In contrast, 57 (77%) of 74 HBV specimens showed soluble and membrane-bound HLA-G expression in hepatocytes, biliary epithelial cells or both. No associations between the intensity of HLA-G expression and patient age or gender, HBeAg status, severity of liver fibrosis, and grade of histological findings were observed. Although significance was not reached (P = 0.180), patients exhibiting HLA-G expression presented a higher median HBV DNA viral load (105 copies/mL) than those who did not express HLA-G (103.7 copies/mL). These results indicate that HLA-G is expressed in most cases of chronic HBV infection in all stages and may play a role in the persistency of HBV infection.

Significance of topoisomerase III beta expression in breast ductal carcinomas: strong associations with disease-specific survival and metastasis

Topoisomerases are ubiquitous nuclear enzymes that regulate DNA structure in eukaryotic cells. The role of topoisomerase III beta, the newest member of the topoisomerase family, in the clinical outcome of breast cancer is still poorly understood. This study aims to investigate the immunoexpression of topoisomerase III beta in breast cancer and its relationships with clinicopathologic features and immunohistochemical markers of prognostic significance in breast pathology. Using tissue microarrays containing 171 cases of primary invasive breast cancer, we analyzed the immunoexpression of topoisomerase III beta, estrogen receptor, progesterone receptor, HER-2, BRCA-1, p53, and Ki67. Immunostaining for topoisomerase III beta was found in 33.9% of breast carcinomas, and immunopositivity was correlated with distant metastasis (P = .036) and death (P = .006). Decreased expression of topoisomerase III beta correlated with low expression of Ki67 (P < .001) and negativity for HER-2 (P < .001), BRCA-1 (P = .001), and p53 (P < .001). In the multivariate analysis, topoisomerase Hip expression was a significant predictor of survival (hazard ratio, 3.006 [95% confidence interval, 1.582-5.715]; P = .001). In conclusion, topoisomerase III beta expression can be a useful marker in assessing the prognosis of patients with breast cancer and is an independent predictor of survival. (C) 2010 Elsevier Inc. All rights reserved.

Mesial temporal lobe epilepsy: Clinical and neuropathologic findings of familial and sporadic forms

Purpose: To evaluate the clinical and hippocampal histological features of patients with mesial temporal lobe epilepsy (MTLE) in both familial (FMTLE) and sporadic (SMTLE) forms. Methods: Patients with FMTLE (n = 20) and SMTLE (n = 39) who underwent surgical treatment for refractory seizures were studied at the University of Sao Paulo School of Medicine at Ribeirao Preto. FMTLE was defined when at least two individuals in a family had clinical diagnosis of MTLE. Hippocampi from all patients were processed for Nissl/HE and Timm`s stainings. Both groups were compared for clinical variables, hippocampal cell densities, and intensity of supragranular mossy fiber staining. Results: There were no significant differences between FMTLE and SMTLE groups in the following: age at the surgery, age of first usual epileptic seizure, history of initial precipitating injury (IPI), age of IPI, latent period, ictal and interictal video-EEG patterns, presence of hippocampal atrophy and signal changes at MRI, and postoperative outcome. In addition, no differences were found in cell densities in hippocampal cornu ammonis subfields (CA1, CA2, CA3, CA4), fascia dentata, polymorphic region, subiculum, prosubiculum, and presubiculum. However, patients with SMTLE had greater intensity of mossy fiber Timm`s staining in the fascia dentata-inner molecular layer (p < 0.05). Discussion: Patients with intractable FMTLE present a clinical profile and most histological findings comparable to patients with SMTLE. Interestingly, mossy fiber sprouting was less pronounced in patients with FMTLE, suggesting that, when compared to SMTLE, patients with FMTLE respond differently to plastic changes plausibly induced by cell loss, neuronal deafferentation, or epileptic seizures.

A DNA vaccine candidate encoding the structural prM/E proteins elicits a strong immune response and protects mice against dengue-4 virus infection

A DNA vaccine expressing dengue-4 virus premembrane (prM) and envelope (E) genes was produced by inserting these genes into a mammalian expression plasmid (pCI). Following a thorough screening, including confirmation of protein expression in vitro, a recombinant clone expressing these genes was selected and used to immunize BALB/c mice. After 3 immunizations all the animals produced detectable levels of neutralizing antibodies against dengue-4 virus. The cytokines levels and T cell proliferation, detected ex vivo from the spleen of the immunized mice, showed that our construction induced substantial immune stimulation after three doses. Even though the antibody levels, induced by our DNA vaccine, were lower than those obtained in mice immunized with dengue-4 virus the levels of protection were high with this vaccine. This observation is further supported by the fact that 80% of the vaccine immunized group was protected against lethal challenge. In conclusion, we developed a DNA vaccine employing the genes of the prM and E proteins from dengue-4 virus that protects mice against this virus. (C) 2010 Elsevier Ltd. All rights reserved.

Strong Grobner bases for polynomials over a principal ideal ring

Grobner bases have been generalised to polynomials over a commutative ring A in several ways. Here we focus on strong Grobner bases, also known as D-bases. Several authors have shown that strong Grobner bases can be effectively constructed over a principal ideal domain. We show that this extends to any principal ideal ring. We characterise Grobner bases and strong Grobner bases when A is a principal ideal ring. We also give algorithms for computing Grobner bases and strong Grobner bases which generalise known algorithms to principal ideal rings. In particular, we give an algorithm for computing a strong Grobner basis over a finite-chain ring, for example a Galois ring.

Cdc25B activity is regulated by 14-3-3

In the G2 phase cell cycle checkpoint arrest, the cdc25-dependent activation of cyclin B/cdc2, a critical step in regulating entry into mitosis, is blocked. Studies in yeast have demonstrated that the inhibition of cdc25 function involves 14-3-3 binding to cdc25, In humans, two cdc25 isoforms have roles in G2/M progression, cdc25B and cdc25C, both bind 14-3-3, Abrogating 14-3-3 binding to cdc25C attenuates the G2 checkpoint arrest, but the contribution of 14-3-3 binding to the regulation of cdc25B function is unknown. Here we demonstrate that high level over-expression of cdc25B in G2 checkpoint arrested cells can activate cyclin B/cdc2 and overcome the checkpoint arrest. Mutation of the major 14-3-3 binding site, S323, or removal of the N-terminal regulatory domain are strong activating mutations, increasing the efficiency with which the mutant forms of cdc25B not only overcome the arrest, but also initiate aberrant mitosis, We also demonstrate that 14-3-3 binding to the S323 site on cdc25B blocks access of the substrate cyclin/cdks to the catalytic site of the enzyme, thereby directly inhibiting the activity of cdc25B, This provides direct mechanistic evidence that 14-3-3 binding to cdc25B can regulate its activity, thereby controlling progression into mitosis.

A small disturbance in the strong vortex flow

A small disturbance in the axisymmetric, bathtub-like flow with strong vorticity is considered and the asymptotic representation of the solution is found. It is shown that if the disturbance is smaller than a certain critical scale, the conventional strong vortex approximation cannot describe the field generated by the disturbance not only in the vicinity of the disturbance but also at the distances much larger than the critical scale. (C) 2001 American Institute of Physics.

Moderately strong vorticity in a bathtub-type flow

Theoretical and numerical analysis is performed for an inviscid axisymmetric vortical bathtub-type flow. The level of vorticity is kept high so that the image of the flow on the radial-axial plane (r-z plane) is not potential. The most significant findings are: (1) the region of validity of the strong vortex approximation is separated from the drain by a buffer region, (2) the power-law asymptote of the stream function, specified by Delta Psi similar to r(4/3) Deltaz, appears near the axis when vorticity in the flow is sufficiently strong and (3) the local Rossby number in the region of the 4/3 power-law the initial vorticity level in the flow and the global Rossby number.

Targeting of EBNA1 for rapid intracellular degradation overrides the inhibitory effects of the Gly-Ala repeat domain and restores CD8+T cell recognition

Epstein-Barr virus (EBV)-encoded nuclear antigen 1 (EBNA1) includes a unique glycine-alanine repeat domain that inhibits the endogenous presentation of cytotoxic T lymphocyte (CTL) epitopes through the class I pathway by blocking proteasome-dependent degradation of this antigen. This immune evasion mechanism has been implicated in the pathogenesis of EBV-associated diseases. Here, we show that cotranslational ubiquitination combined with N-end rule targeting enhances the intracellular degradation of EBNA1, thus resulting in a dramatic reduction in the half-life of the antigen. Using DNA expression vectors encoding different forms of ubiquitinated EBNA1 for in vivo studies revealed that this rapid degradation, remarkably, leads to induction of a very strong CTL response to an EBNA1-specific CTL epitope. Furthermore, this targeting also restored the endogenous processing of HLA class I-restricted CTL epitopes within EBNA1 for immune recognition by human EBV-specific CTLs. These observations provide, for the first time, evidence that the glycine-alanine repeat-mediated proteasomal block on EBNA1 can be reversed by specifically targeting this antigen for rapid degradation resulting in enhanced CD8+ T cell-mediated recognition in vitro and in vivo.

Clinical supervision in four mental health professions: A review of the evidence

This paper examines a range of theoretical issues and the empirical evidence relating to clinical supervision in four mental health professions, namely clinical psychology, occupational therapy, social work, and speech pathology. Despite the widespread acceptance of the value of supervision among practitioners and the large quantity of literature on the topic, there is very little empirical evidence in this area. It is not clear whether supervision actually produces a change in clinician behaviour, nor whether it produces benefits in terms of client outcomes. To date, there is insufficient evidence to demonstrate which styles of supervision are most beneficial for particular types of staff, in terms of their level of experience or learning style. The data suggest that directive forms of supervision, rather than unstructured approaches, are preferred by relatively inexperienced practitioners, and that experienced clinicians also value direct supervision methods when learning new skills or dealing with complex or crisis situations. The available evidence suggests that supervisors typically receive little training in supervision methods. However, to date, we have little information to guide us as to the most effective ways of training supervisors. While acknowledging the urgent need for research, the paper concludes that supervision is likely to form a valuable component of professional development for mental health professionals.

Relationships between non-occupational cadmium exposure and expression of nine cytochrome P450 forms in human liver and kidney cortex samples

This study was undertaken to assess associations between age, gender, cigarette smoke and non-workplace cadmium exposure, and liver pathology and inter-individual variation in cytochrome P450 (CYP) expression in human tissues. Autopsy specimens of twenty-eight Queensland residents whose ages ranged from 3 to 89 years were analyzed for the presence of nine CYP protein isoforms by immunoblotting. All subjects were Caucasians and their liver cadmium contents ranged from 0.11 to 3.95 kg/g wet weight, while their kidney cadmium contents were in the range of 2 to 63 mug/g wet weight. CYP1A2, CYP2A6, CYP2D6, CYP3A4, and CYP3A5 were detected in liver but not in kidney, and CYP1A1 and CYP1B1 were not found in liver or kidney. Lowered liver CYP2C8/19 protein contents were found to be associated with liver pathology. Importantly, we show elevated levels of CYP2C9 protein to be associated with cadmium accumulation in liver. No mechanism that explains this association is apparent, but there are two possibilities that require further study. One is that variation in CYP2C9 protein levels may be, in part, attributed to an individual's non-workplace exposure to cadmium, or an individual's CYP2C9 genotype may be a risk factor for cadmium accumulation. A positive correlation was found between liver CYP3A4 protein and subject age. Levels of liver CYPIA2 protein, but not other CYP forms, were increased in people more exposed to cigarette smoke, but there was no association between CYPIA2 protein and cadmium. CYP2A6 protein was found in all liver samples and CYP2A6 gene typing indicated the absence of CYP2A6 null allele (CYP2A6(D)) in this sample group, confirming very low prevalence of homozygous CYP2A6(D) in Caucasians. CYP2A6 gene types W/W, WIC, and CIC were not associated with variations in liver microsomal CYP2A6 protein. CYP2D6 protein was absent in all twenty-five kidney samples tested but was detectable in liver samples of all but two subjects, indicating the prevalence of the CYP2D6 null allele (CYP2D6(D)) in this sample group to be about 7%, typical of Caucasian populations. (C) 2001 Elsevier Science Inc. All rights reserved.

Australia, the United States and a 'China growing strong': managing conflict avoidance

How to deal with a rising China constitutes one of the most seminal challenges facing the ANZUS alliance since its inception a half a century ago. Australia must reconcile its geography and economic interests in Asia with its post-war strategic and historic cultural orientation towards the United States. It must succeed in this policy task without alienating either Beijing or Washington in the process. The extent to which this is achieved will shape Australia's national security posture for decades to come. Three specific components of the 'Sino-American-Australian' triangle are assessed here: the future of Taiwan, the American development of a National Missile Defence (NMD), and the interplay between Sino-American power balancing and multilateral security politics. The policy stakes for Australia and for the continued viability of ANZUS are high in all three policy areas as a new US Administration takes office in early 2001. The article concludes that Australia's best interest is served by applying deliberate modes of decisionmaking in its own relations with both China and the US and by facilitating consistent and systematic dialogue and consultations with both of those great powers on key strategic issues.